Organic peroxides are very unstable materials. Even in a dry crystalline state, organic peroxides decompose relatively fast (Ref. 1 and 2). The rate of thermal degradation increases exponentially with an increase of temperature. In solution, the rate of thermal degradation depends on the type of the solvent used, concentration of benzoyl peroxide solubility in the solvent system (Ref. 4). This compound is least stable in PEG 400. Stability is improved when water is added to PEG 400. Similar solvent effects can be observed in suspension. For benzoyl peroxide suspensions in PEG 400 and PEG 400/water blends, benzoyl peroxide stability is dependent on solubility, with improved stability occurring in blends where the benzoyl peroxide is least soluble. Thus, formulations of solubilized benzoyl peroxide in pharmaceutically acceptable solvents are unlikely to show good stability. However, suspension formulations should be reasonably stable if selected vehicle is provides low BP solubility (Ref. 4).
At 50° C. the potency of benzoyl peroxide suspension in polyethylene glycol ointment base decreases from 5% to less than 1% in 5 days. Benzoyl peroxide decomposes very quickly (first-order K value 0.028 day−1 at 24° C.) in polyethylene glycol ointment base (Ref. 5).
Benzoyl peroxide is quite unstable in the presence of nucleophilic agents and certain acidic substances. BP is destroyed rapidly (within 1 month) in the presence of ethanol and acidic chelating agents, when stored at 30° C. or 40° C. (Ref. 6). An increase of the pH also dramatically accelerates degradation.
Organic peroxides are very strong oxidants. They can be used as radical initiators of polymerization, bleach agents and chemical etching components. Since peroxides easily react with different types of molecules such as unsaturated compounds, amines and amino acids, proteins, dyes, oils, thiols, etc., it is difficult to obtain stabilized peroxide solutions. The stability of peroxides in solution is inversely related to their solubility in the solvent system—i.e. the less of peroxide is in dissolved state, the more stable is the preparation (Refs. 1 and 4).
Peroxides possess strong antibacterial properties (Ref. 7). A higher stability of peroxides prevents the undesirable degradation and leads to a longer-lasting antimicrobial effects.
Attempts at stabilizing benzoyl peroxide in solution using different stabilizers, such as chelating agents, pH adjusters, solvent mixtures and other additives (acetanilide, benzoic acid, chlorhydroxyquinoline, and hydroxyquinoline) have not been successful (Ref. 5 and 6). Addition of chlorhydroxyquinoline slightly improves stability, but this improvement is not significant enough to provide a solution, stable for more than 1 month at room temperature.
In U.S. Pat. No. 4,844,886, Hartmann and Kohler use bisabolol to stabilize hydrogen peroxide in an emulsion-surfactant system. However this approach is not suitable for water-insoluble organic peroxides.
Benzoyl peroxide is one of the most widely used compounds for acne treatment due to significant antimicrobial activity, mild keratolytic and duct opening properties and low cost. The actions include a topical antimicrobial effect against infecting bacteria, the removal of the horny layer of the epidermis, as well as the removal of thickened sebum and other debris clogging follicular pores.
Benzoyl peroxide, especially in suspensions, has the potential to irritate the skin when applied at concentrations suitable for effective acne treatment. Formulations combining commonly used surfactants such as sodium laurylsulfate with BP, may exaggerate this irritating effect. To decrease irritability, moisturizers and emollients are often used in combination with mild non-ionic surfactants. U.S. Pat. No. 4,056,611, describes compositions containing a non-ionic surfactant, a short chain of alcohol and water. In U.S. Pat. No. 4,725,429, Scott et al., present a composition of benzoyl peroxide in silicon oil, combined with surfactants and high-alkyl alcohols to provide increased bioavailability due to the occlusive properties of the vehicle.
The extremely low solubility of benzoyl peroxide in a water medium has motivated investigators to develop solubilized formulations, which provide a high concentration of the oxidizer at the point of action, i.e. clogged follicle or blemish spot.
U.S. Pat. No. 4,923,900, discloses compositions containing BP, water and a water-miscible solvent with a boiling point higher than that of water. Dimethylisosorbide is indicated as a particularly useful solvent in the disclosed compositions. The disclosed compositions are indicated for the treatment of skin conditions such as acne and seborrhea, dermatophyte infection, reactions to irritative plant contactants such as the oleoresins of poison ivy and in the prevention of the development of offensive body odour. Nevertheless, in formulations prepared according to U.S. Pat. No. 4,923,900, only a small percentage of the BP remains in a dissolved state, explaining why the treatment efficacy is much lower than would be indicated for a totally dissolved oxidant.
Few examples of solubilized benzoyl peroxide formulations exist. Decker et al. in U.S. Pat. No. 4,925,666, describe a solubilized benzoyl peroxide formulation in polymeric siloxanes at elevated temperature.
Benzoyl Peroxide forms clear solutions, but requires high concentrations of volatile organic solvents such as acetone and isopropyl alcohol to achieve this. The solutions obtained must be stored under refrigeration. Evaporation of the solvent after application of the solution to the epidermis may cause crystallization of the drug on the skin surface.
Popp and Stiefel in U.S. Pat. No. 6,433,024, disclose a composition of benzoyl peroxide in a vehicle comprising isosorbide ester and water and containing surfactants, hydroxyacids and polyvinylpyrrolidone carboxylate to improve solubility and decrease irritation. None of the known currently available topical formulations of BP possesses the optimal combination of effective anti-acne properties, a non-irritating composition and a formulation stability that provides for efficacious treatment of acne conditions and satisfactory long-term storage stability at an elevated temperature. There remains a need for a stable formulation of solubilized BP to increase treatment efficacy and to decrease skin irritability.